Vitamin D receptor gene polymorphisms and the risk of multiple sclerosis: An updated meta-analysis.
The association between vitamin D receptor (VDR) gene polymorphisms and multiple sclerosis (MS) has been extensively studied, but results were controversial.
This meta-analysis aimed to confirm whether VDR gene polymorphisms were associated with MS. Meta-analysis on the association between MS and VDR ApaI, BsmI, TaqI and FokI polymorphisms were conducted using allelic contrast, recessive, homozygotes and dominant models. Data were extracted by standardized forms and odds ratios (OR) with 95% confidence intervals (CI) were calculated using the random effects model if the results were heterogeneous. Stratification analysis by the selected study characteristics were performed to detect potential source of heterogeneity.
A total of 21 relevant studies involving 3593 MS patients and 3917 controls were included in the analysis. The association between TaqI polymorphism and MS risk was significant in the homozygous model (p = 0.006) indicated a significant protective effect of TT TaqI genotype. High latitude (40.1-50°N) was also found markedly influenced TaqI polymorphism and MS risk in the recessive and homozygous models (p = 0.045 and p = 0.015, respectively). Additionally, Asian or low latitude (20.1-30°N) people with ApaI homozygous genotype, '> 2013' publication year people in the allele contrast and dominant models of FokI, '> 40 years' age people with BsmI recessive model also indirectly significantly affected the association between VDR gene polymorphisms and MS risk.
TaqI polymorphism is a significant protective factor for MS. However, the associations between ApaI, FokI and BsmI polymorphisms and MS were found only by study characteristics.
The expression of VDR mRNA but not NF-κB surprisingly decreased after vitamin D treatment in multiple sclerosis patients.
BACKGROUND AND PURPOSE:
The aim of this study was to investigate the expression levels of vitamin D receptor (VDR) and NF-κB mRNAs in vitamin D (VD) supplemented multiple sclerosis (MS) patients.
RRMS patients received 50,000 IU vitamin D3/week as an intra-muscular injection for 2 months. Blood samples were obtained from 30 MS patients before and after VD supplementation and 32 healthy individuals, and then VDR and NF-κB mRNA levels were measured by real time PCR method and analyzed with independent and paired t-tests. Moreover, some correlations were performed between the expression levels of selected genes and some clinical features of MS and control groups.
Surprisingly, the expression level of VDR mRNA significantly decreased after 2 months supplementation with VD in our selected patients and in contrast, the level of serum 25(OH) D increased after supplementation. Although, we didn't find any significant difference in the expression level of NF-κB gene before and after treatment with VD, its expression significantly decreased in untreated MS cases compared with healthy controls.
In conclusion, we found some new evidences from the molecular mechanism of vitamin D effectiveness in MS treatment. Also, we need more functional studies to find the effect of VD on the expression level of VDR mRNA.
Evaluation of vitamin D3 intakes up to 15,000 international units/day and serum 25-hydroxyvitamin D concentrations up to 300 nmol/L on calcium metabolism in a community setting
Supplementation by the general public with vitamin D at doses above the Tolerable Upper Level of Intake (UL) is becoming quite common. The objective of the current analysis was to characterize the effect of vitamin D supplementation at doses up to 15,000 IU/d in a community-based program on vitamin D status, calcium homeostasis as well as on kidney, liver and immune function. We evaluated data collected for 3,882 participants in a community program for whom there were blood measurements at program entry and at follow-up within 6–18 months between 2013 and 2015. Participants were supplemented with a wide range of vitamin D doses (1,000 – 15,000 IU/d) aimed at achieving serum 25-hydroxyvitamin D [25(OH)D] levels of at least 100 nmol/L. Serum 25(OH)D concentrations up to 300 nmol/L were achieved without perturbation of calcium homeostasis or incidence of toxicity. Hypercalcemia and hypercalciuria were not related to an increase in 25(OH)D concentrations nor vitamin D dose. To achieve serum 25(OH)D levels >100 nmol/L on average, required vitamin D intakes of 6,000 IU/d for normal Body Mass Index (BMI), 7,000 IU/d for overweight and 8,000 IU/d for obese. Doses of vitamin D in excess of 6,000 IU/d were required to achieve serum 25(OH)D concentrations above 100 nmol/L, especially in individuals who were overweight or obese without any evidence of toxicity. Serum 25(OH)D concentrations up to 300 nmol/L were found to be safe.
http://www.tandfonline.com/doi/full/10. ... 3?fref=gc&
Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis
Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (−0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10−88). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78–2.78, p = 1.26 × 10−12). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19–1.64, p = 2.63 × 10−5) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
http://www.sciencedirect.com/science/ar ... 971730277X
Remission of Severe Myasthenia Gravis After Massive-Dose Vitamin D Treatment
Vitamin D has been shown to be related to autoimmune diseases, such as multiple sclerosis and psoriasis. Correlations have been reported between vitamin D levels and prevalence and severity of other autoimmune disorders, and also between vitamin D therapy and disease improvement and remission.
This is a case report of a patient with severe and refractory myasthenia gravis (MG) who followed a “high-dose vitamin D treatment”, a massive-dose treatment (80 000 to 120 000 IU/day) promoted by a medical center in Brazil (but still not proven), and she had her first complete remission after this type of treatment with increased vitamin D serum levels (400 to 700 ng/mL).
This case report may reinforce the reported correlation between vitamin D level and disease severity and introduces a possible new use for vitamin D as a potential target for treating autoimmune diseases. We recommend large, double-blind, placebo-controlled, randomized studies using high-dose vitamin D treatment for refractory autoimmune diseases to reliably assess this pharmacotherapy target for these diseases.
1,25-Dihydroxyvitamin-D3 induces brain proteomic changes in cuprizone mice during remyelination involving calcium proteins.
Dietary supplementation of vitamin D is commonly recommended to patients with multiple sclerosis. We recently found that high-dose of the hormonally active 1,25-dihydroxyvitamin-D3 (1,25D) promotes myelin repair in the cuprizone model for de- and remyelination. In the present study, we quantified 5062 proteins, of which 125 were differentially regulated in brain tissue from 1,25D treated mice during remyelination, compared to placebo. Proteins upregulated in the early remyelination phase were involved in calcium binding, e.g. calretinin (>1.3 fold, p < 0.005), S10A5 and secretagogin, and involved in mitochondrial function, e.g. NADH-ubiquinone oxidoreductase chain 3, and acyl-coenzyme A synthetase. Calretinin, S10A5 and secretagogin expression levels were characterized using immunohistochemistry. Calretinin immunoreactivity was significantly increased (>3 fold, p = 0.016) in the medial septal nuclei of 1,25D treated mice in the early remyelination phase. Our results indicate that vitamin D may influence remyelination by mechanisms involving an increase in calretinin expression and potentially other calcium binding proteins.
Association of CYP2R1 rs10766197 with MS risk and disease progression.
MS is a neurodegenerative autoimmune disease resulting from a complex interaction of genetic and environmental factors. Among these, vitamin D and genetic variants associated with vitamin D-metabolism gain great attention. The aim of our study was to assess five SNPs in NADSYN1 and CYP2R1 genes in relation to serum 25-OH-vitamin D3 levels in MS patients and controls.
25-OH-vitamin D3 levels and genotyping of CYP2R1- and NADSYN1-SNPs were investigated both in MS patients and in healthy controls.
The analysis revealed lower 25-OH-vitamin D3 concentrations in MS patients than in controls and an association of rs10766197 CYP2R1 SNP with MS risk. After stratifying MS patients according to gender, we found that the minor allele A of rs10766197 had a higher frequency in men in comparison to women affected by MS. Additionally, the presence of allele A in men was associated with disease progression, assessed by EDSS and MSSS scores.
The findings of our study open new perspectives for a role of CYP2R1 in both risk and progression of MS, with sex-related differences.
A phase I/II dose-escalation trial of vitamin D3 and calcium in multiple sclerosis.
Low vitamin D status has been associated with multiple sclerosis (MS) prevalence and risk, but the therapeutic potential of vitamin D in established MS has not been explored. Our aim was to assess the tolerability of high-dose oral vitamin D and its impact on biochemical, immunologic, and clinical outcomes in patients with MS prospectively.
An open-label randomized prospective controlled 52-week trial matched patients with MS for demographic and disease characteristics, with randomization to treatment or control groups. Treatment patients received escalating vitamin D doses up to 40,000 IU/day over 28 weeks to raise serum 25-hydroxyvitamin D [25(OH)D] rapidly and assess tolerability, followed by 10,000 IU/day (12 weeks), and further downtitrated to 0 IU/day. Calcium (1,200 mg/day) was given throughout the trial. Primary endpoints were mean change in serum calcium at each vitamin D dose and a comparison of serum calcium between groups. Secondary endpoints included 25(OH)D and other biochemical measures, immunologic biomarkers, relapse events, and Expanded Disability Status Scale (EDSS) score.
Forty-nine patients (25 treatment, 24 control) were enrolled [mean age 40.5 years, EDSS 1.34, and 25(OH)D 78 nmol/L]. All calcium-related measures within and between groups were normal. Despite a mean peak 25(OH)D of 413 nmol/L, no significant adverse events occurred. Although there may have been confounding variables in clinical outcomes, treatment group patients appeared to have fewer relapse events and a persistent reduction in T-cell proliferation compared to controls.
High-dose vitamin D (approximately 10,000 IU/day) in multiple sclerosis is safe, with evidence of immunomodulatory effects.
Physician-Scientist Building Legacy of Research on MS-Vitamin D Link
University of Maryland Rounds features clinical and research updates from the University of Maryland School of Medicine and the University of Maryland Medical Center.
Intended for physicians, Rounds contains contact information to learn more about the clinical and research advances featured in each issue. It is printed three times a year and distributed monthly via email.
With vitamin D’s health benefits for conditions such as heart disease, cancer and diabetes becoming increasingly clear, a University of Maryland physician-scientist has spent years plumbing the potential role of the “sunshine vitamin” in the development, prevention or treatment of multiple sclerosis in ways that directly help his own MS patients.
http://www.umm.edu/programs/neuroscienc ... min-d-link
Multiple sclerosis: Vitamin D deficiency may predict onset
A new, large-scale study in Finnish women suggests that vitamin D deficiency can significantly raise the risk of multiple sclerosis, which makes it a reliable predictive marker for the disease. By contrast, correcting this deficiency may reduce the risk.
It is not currently known what causes multiple sclerosis (MS), a debilitating neurological disease that is estimated to affect 400,000 people in the United States.
However, it is known that women are at much higher risk of developing the disease than men. And new research in a large sample of women has found a risk factor: low vitamin D levels.
The new study was published in the journal Neurology, and the first author of the paper is Dr. Kassandra Munger, of the Harvard T.H. Chan School of Public Health in Boston, MA.
Dr. Munger explains that to date, "There have only been a few small studies suggesting that levels of vitamin D in the blood can predict risk." But the new research examines a much larger cohort.
Vitamin D deficiency is associated with disability and disease progression in multiple sclerosis patients independently of oxidative and nitrosative stress
• Vitamin D deficiency is associated with disability and progression of disease in multiple sclerosis patients.
• Vitamin D is not associated with oxidative and nitrosative stress in patients with multiple sclerosis.
• Vitamin D deficiency may contribute with 11.5% of increase in EDSS.
• Patients with 25(OH)D < 20 ng/mL showed higher EDSS and MSSS.
• The present study showed a negative association between low levels of NOx and total antioxidant capacity and MS.
The aim of this study was to assess vitamin D status in patients with multiple sclerosis (MS) and to evaluate whether it was associated with oxidative and nitrosative stress (O&NS) markers and disability. This study included 137 patients with MS and 218 healthy controls. The markers evaluated were serum levels of 25-hydroxyvitamin D, lipid hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter TRAP/UA. Patients with 25(OH)D < 20 ng/mL showed higher EDSS (p = 0.016), MSSS (p = 0.005) and lower AOPP (p = 0.046) than those with 25(OH)D ≥ 20 ng/mL. After the binary logistic regression analyses, EDSS and MSSS remained significantly associated with vitamin D deficiency. We showed that lower levels of 25(OH)D were associated with higher EDSS and MSSS independently of variables such as O&NS, age, sex, body mass index, ethnicity, MS therapy, use of interferon beta, and clinical forms of MS (odds ratio: 1.380, 95% confidence interval 1.030–1.843, p = 0.031). Moreover, the study showed an association between serum levels of 25(OH)D and EDSS (r2 = 0.115, p = 0.002), demonstrating that 25(OH)D may contribute with 11.5% of increase in EDSS. Our results suggest that vitamin D deficiency may be considered one of the predictors of the disability in MS patients, independently of their redox status and influence the progression of disability in MS.
http://www.jns-journal.com/article/S002 ... X/fulltext
Preventing multiple sclerosis
To (take) vitamin D or not to (take) vitamin D?
Ruth Ann Marrie, MD, PhD and Christopher A. Beck, PhD
Over 2 million persons worldwide have multiple sclerosis (MS),1 and the burden of the disease for affected individuals and society is substantial. A recent study estimated that by 2031, 133,635 Canadians would be living with MS, and that the direct costs of their care would reach a staggering $2 billion annually.2 Therefore, identifying modifiable risk factors for MS remains vitally important. Researchers still seek to firmly demonstrate a causal role for vitamin D, a biologically plausible etiologic factor which is modifiable. Vitamin D receptors are ubiquitous, being expressed on immune cells and in the CNS; immune responses are affected by variations in 25-hydroxyvitamin D (25[OH]D) levels; and 1,25-dihydroxycholecaliferol can prevent the emergence of experimental autoimmune encephalomyelitis,3,4 an animal model of demyelinating disease. However, epidemiologic studies have often been hindered by the inability to demonstrate temporality; that is, that the exposure to inadequate 25(OH)D occurred before the onset of MS.
http://www.neurology.org/content/early/ ... 0000004506
Vitamin D supplementation differentially affects seasonal multiple sclerosis disease activity
Low ultraviolet-B (UVB) radiation causes hypovitaminosis D, which is a known risk factor for multiple sclerosis (MS) and associated with MS disease activity. Our objective is to test whether vitamin D supplementation is most effective in lowering disease activity during the period of the year with low UVB radiation and consequently low serum 25-hydroxyvitamin D3 (25(OH)D3) concentration.
Retrospective analysis of medical records from our outpatient department identified 40 MS patients with available data of at least 6 months before and during oral vitamin D supplementation. Serum 25(OH)D3 concentration was analyzed using immunoassay. UVB radiation data were provided by the local government. Annualized and quarterly relapse rates before and during vitamin D supplementation served as outcome parameters.
During vitamin D supplementation (18,950 international units/week (mean, SD 3,397)), serum 25(OH)D3 concentration increased by 51 nmol/L and the UVB-related seasonal variability in 25(OH)D3 levels ceased (rho = −0.13, p > .05). Furthermore, the annualized relapse rate decreased by approximately 50%. This was almost solely driven by the prominent reduction in the quarterly relapse rate in late winter/early spring, when 25(OH)D3 levels of nonsupplemented patients were the lowest.
Our study demonstrated the modulation of seasonal MS disease activity through vitamin D supplementation. Given the prominent reduction in the quarterly relapse rate in late winter/early spring, our data indicate a beneficial effect of supplementing MS patients with vitamin D, especially during this period of the year.
http://onlinelibrary.wiley.com/doi/10.1 ... 3.761/full
Restored Vision Through Vitamin D Megadoses
We asked our readers to help us document how they use vitamin D to treat their conditions. One respondent reported: I am 65 years old and live in Minnesota. I began taking 5K IU/day in 2010, and have not experienced a respiratory illness since. In October 2012, I upped my dose to 50K IU/day for a couple of weeks, then 30K IU/day for another couple of weeks, and then 20K day for two years. I now take 15K IU/day.
In December 2012, my hairdresser said the roots of my hair were darkening, and the following month that hair was growing into my bald spot. In 1988 I lost most of the sight in my right eye due to idiopathic optic neuritis. In September 2013, I started to notice pattern and color in an area formerly without sight. By August 2014, I had recovered nearly all the sight in my right eye; my vitamin D level was measuring at 104 ng/ml. My physician says that the optic nerve has remyelinated, and he says he is unaware of any other case where this has occurred 25 years later.
I attribute recovery of sight to high-dose vitamin D, as nothing else has changed. I took 5k IU/day for nearly two years without any noticeable effects other than no respiratory illness, in contrast to previous years when I had two or three colds per winter. The first evidence of darkening of hair occurred about 8 weeks after I started the 20k IU/day but continued for a couple of years. I haven't noticed much change in the past year. I did not notice the changes to vision until about 10 months after taking 20k IU/day, and the vision gradually improved over the next 12 months. As stated earlier, it is now almost completely back to normal.
An important point is that all of the more remarkable effects occurred while I was taking doses of at least 20,000 IU per day. I think this is important because it suggests the dosages necessary for remyelination of nerves and the duration of treatment. It doesn't happen overnight! And, it is obvious, different effects occurred on different timetables. Hence my strong interest in the health effects of vitamin D, and my fascination with the efficacy of very high dose D on otherwise refractory illnesses and autoimmune diseases.
http://www.spiritofchange.org/Journal-o ... s.facebook
Interesting Case Study: High Dose Vitamin D Protocol in Treating Aggressive RMS
Thursday, May 25, 2017
B2 (New Orleans Convention Center)
Denise R Bruen, ANP-BC, MSCN , Neurology, University of Virginia MS Clinic, Charlottesville, VA
2017 CMSC Abstract Poster Presentation
MS research has yet to define the appropriate amount or Vitamin D levels our MS patients should strive for. How much is too much? How little is not protective?
What is the risk of taking too much Vitamin D? Are we actually underutilizing a possible low risk treatment or adjunctive supplement?
Many of our patients are often dubious about risk and benefits of our current DMTs especially if they feel otherwise healthy. Occasionally we see a distressing brain MRI with many active MS lesions in an asymptomatic patient. It can be difficult to convince these patients to be on a potentially risky medication. Sometimes they seek alternative therapies. Could the answer or missing puzzle piece be Vitamin D hypovitaminosis?
This is the case study of J.B. a 40 year old Caucasian woman who had been lost to follow up, previously on an IM Interferon agent. Updated MRIs times two, both on and off DMT, showed multiple enhancing lesions. Not wanting to remain on or try a different DMT she elected to start a high dose Vitamin D protocol under supervision of an out of state provider. MRIs since have been remarkably quiet. *MRIs over the past 2 years to be shared on poster.
Is J.B.’s case regression to the norm or has high dose Vitamin D been effective as her sole treatment. I argue as a MS community we should decide on an appropriate Vitamin D level and perhaps be pushing higher doses as a supplemental therapy to stabilize our patients.
https://cmsc.confex.com/cmsc/2017/webpr ... r5110.html
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